Antihyperalgesic Effect of Buprenorphine Involves Nociceptin/Orphanin FQ Peptide–Receptor Activation in Rats With Spinal Nerve Injury–Induced Neuropathy

Takahashi, Tomoko; Okubo, Kazumasa; Kojima, Shota; Nishikawa, Hiroyuki; Takemura, Motohide; Tsubota-Matsunami, Maho; Sekiguchi, Fumiko; Kawabata, Atsufumi

doi:10.1254/jphs.13029sc

Cited by 12 publications

(5 citation statements)

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“…of morphine or buprenorphine attenuates hypersensitivity in neuropathic rats, here, we report that although the TLR4 antagonists actually enhanced buprenorphine's analgesic effect, in contrast, the effect of morphine was not enhanced. Morphine suppresses neuropathic pain via opioid receptors, while buprenorphine also activates nociceptin/orphanin FQ peptide (NOP) receptors [ 41 ]. Preliminary data published to date suggests there is a link between TLR4 activation by an exogenous ligand (LPS) and NOP upregulation because they indicate that antagonism of TLR4 also attenuates the enhancement of NOP levels [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

et al. 2016

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Accumulating evidence indicates that microglial TLR2 and TLR4 play a significant role in nociception. Experiments were conducted to evaluate the contribution of TLR2 and TLR4 and their adaptor molecules to neuropathy and their ability to amplify opioid effectiveness. Behavioral tests (von Frey's and cold plate) and biochemical (Western blot and qRT-PCR) analysis of spinal cord and DRG tissue were conducted after chronic constriction injury (CCI) to the sciatic nerve. Repeated intrathecal administration of LPS-RS (TLR2 and TLR4 antagonist) and LPS-RS Ultrapure (TLR4 antagonist) attenuated allodynia and hyperalgesia. Biochemical analysis revealed time-dependent upregulation of mRNA and/or protein levels of TLR2 and TLR4 and MyD88 and TRIF adaptor molecules, which was paralleled by an increase in IBA-1/CD40-positive cells under neuropathy. LPS-RS and LPS-RS Ultrapure similarly influenced opioid analgesia by enhancing the effectiveness of buprenorphine but not morphine. Summing up, in light of their upregulation over the course of pain, both TLR2 and TLR4 may indeed play a significant role in neuropathy, which could be linked to the observed activation of IBA-1/CD40-positive cells. Blockade of TLR2 and TLR4 produced analgesia and enhanced buprenorphine's effectiveness, which suggests that they may be a putative target for future pharmacological pain relief tools, especially for opioid rotation, when the effect of morphine is tolerated.

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Section: Discussionmentioning

confidence: 99%

Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

et al. 2016

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“…Buprenorphine has been identified as an ORL-1 receptor agonist [12] in addition to being a partial µ-opioid receptor agonist and κ-opioid receptor agonist and antagonist [13,14]. Though major antinociceptive effects of buprenorphine are expressed through µ-opioid receptors, additional antinociceptive efficacy could be caused by ORL-1 receptors in the neuropathic states [31,35]. …”

Section: Discussionmentioning

confidence: 99%

Inferior Alveolar Nerve Transection Enhanced Formalin-Induced Nocifensive Responses in the Upper Lip: Systemic Buprenorphine Had More Antinociceptive Efficacy over Morphine

Kuki

Sugiyo²,

Abe³

et al. 2014

Pharmacology

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This study was designed to investigate the efficacy of a partial μ-opioid agonist, buprenorphine, against the formalin-induced hyperalgesia in the upper lip in chronically inferior alveolar nerve (IAN)-transected rats. Subcutaneous injection of diluted formalin into the upper lip in the IAN-transected rats showed an increased number of pain-related behavior (PRB; face-rubbing behavior) in every phase up to 45 min (p < 0.01) compared with that in the nontransected sham control rats. The numbers of c-Fos-immunoreactive (IR) cells in the superficial layers of the trigeminal nucleus caudalis (VcI/II) at the rostral (0-0.7 mm caudal to the obex) and middle levels (1.4-2.2 mm caudal to the obex) 2 h after the formalin injection in the IAN-transected rats were significantly increased compared with those in the control rats. The PRB in phases 1 and 2 (0-15 and 15-30 min after formalin injection) in rats with preadministration of morphine (3 mg/kg i.p.) or buprenorphine (100 µg/kg i.p.) was significantly (p < 0.05) smaller than those in the control rats. There was no significant difference in the efficacy between morphine and buprenorphine at these doses. The antinociceptive efficacy in phase 2 of buprenorphine (100 µg/kg) was higher (p < 0.05) than that of morphine (3 mg/kg) in the IAN-transected rats. The number of c-Fos-IR cells in the VcI/II at every level (0-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of morphine (3 mg/kg) or buprenorphine (100 µg/kg) in the control rats. In the IAN-transected rats, the number of c-Fos-IR cells in the caudal VcI/II (2.2-3.6 mm caudal to the obex) after formalin injection was significantly decreased (p < 0.01) with preadministration of buprenorphine (100 µg/kg) but not so much (2.2-2.9 mm caudal to the obex, p < 0.05; 2.9-3.6 mm caudal to the obex, p > 0.05) with preadministration of morphine (3 mg/kg). These results indicate that IAN transection enhanced formalin-induced nocifensive responses in the upper lip, the dermatome of the intact nerve neighboring the IAN. Systemic preadministration of buprenorphine had more antinociceptive effects on the formalin-induced nocifensive behavior in the upper lip compared with morphine in the IAN-transected rats.

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“…Furthermore, the gene panel was extended to the opiate receptor-like 1 gene ( OPRL1 ; NCBI ID 4987), located on chromosome 20 and coding for the nociceptin receptor that shows a high degree of structural homology to the classical opioid receptors although opioid peptides or morphine-like compounds have little or no affinity for it [35]. Its endogenous ligand is nociceptin, however, exogenous opioids comprising buprenorphine [36] and its glucuronide metabolites [37] have been shown to exert agonist activity that seems to contribute to their clinical effects, and the nonselective opioid agonist etorphine also binds at the OPRL1 gene product [38], which supports the inclusion of this gene in the present panel.…”

Section: Methodsmentioning

confidence: 99%

Next-generation sequencing of human opioid receptor genes based on a custom AmpliSeq™ library and ion torrent personal genome machine

Kringel

Lötsch

2016

Clinica Chimica Acta

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BackgroundThe opioid system is involved in the control of pain, reward, addictive behaviors and vegetative effects. Opioids exert their pharmacological actions through the agonistic binding at opioid receptors and variation in the coding genes has been found to modulate opioid receptor expression or signaling. However, a limited selection of functional opioid receptor variants is perceived as insufficient in providing a genetic diagnosis of clinical phenotypes and therefore, unrestricted access to opioid receptor genetics is required.MethodsNext-generation sequencing (NGS) workflow was based on a custom AmpliSeq™ panel and designed for sequencing of human genes related to the opioid receptor group (OPRM1, OPRD1, OPRK1, SIGMA1, OPRL1) on an Ion PGM™ Sequencer. A cohort of 79 previously studied chronic pain patients was screened to evaluate and validate the detection of exomic sequences of the coding genes with 25 base pair exon padding. In-silico analysis was performed using SNP and Variation Suite® software.ResultsThe amplicons covered approximately 90% of the target sequence. A median of 2.54 × 106 reads per run was obtained generating a total of 35,447 nucleotide reads from each DNA sample. This identified approximately 100 chromosome loci where nucleotides deviated from the reference sequence GRCh37 hg19, including functional variants such as the OPRM1 rs1799971 SNP (118 A > G) as the most scientifically regarded variant or rs563649 SNP coding for μ-opioid receptor splice variants. Correspondence between NGS and Sanger derived nucleotide sequences was 100%.ConclusionResults suggested that the NGS approach based on AmpliSeq™ libraries and Ion PGM sequencing is a highly efficient mutation detection method. It is suitable for large-scale sequencing of opioid receptor genes. The method includes the variants studied so far for functional associations and adds a large amount of genetic information as a basis for complete analysis of human opioid receptor genetics and its functional consequences.

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Antihyperalgesic Effect of Buprenorphine Involves Nociceptin/Orphanin FQ Peptide–Receptor Activation in Rats With Spinal Nerve Injury–Induced Neuropathy

Cited by 12 publications

References 14 publications

Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

Inferior Alveolar Nerve Transection Enhanced Formalin-Induced Nocifensive Responses in the Upper Lip: Systemic Buprenorphine Had More Antinociceptive Efficacy over Morphine

Next-generation sequencing of human opioid receptor genes based on a custom AmpliSeq™ library and ion torrent personal genome machine

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